JPH0840939A - Preparation of lecithin-containing lipid emulsion - Google Patents

Abstract

PURPOSE:To provide a method of preparing a stabilized lecithin-containing lipid emulsion by preventing the starting lecithin from forming the lamella structure. CONSTITUTION:In the preparation of a lipid emulsion using lecithin as an emulsifier, lecithin and alcohol are admixed to the lipid and oil-soluble components, and the mixture is mixed with the aqueous components to effect emulsification. The alcohol is ethanol or aqueous ethanol. The amount of the ethanol is 0.1 to 10wt.% based on the lipid and the oil-soluble components. The amount of the ethanol is less than 0.5wt.% based on the lipid emulsion. The lipid emulsion is an intravenous injection solution or a drug carrier. Accordingly, regardless of the state of the starting lecithin (liquid crystal, solid or the like), a lipid emulsion containing lecithin is obtained in uniform quality without difference between lots.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an improved method for preparing a fat emulsion using lecithin as an emulsifier. Specifically, the present invention relates to a method of effectively utilizing lecithin for emulsification, for example, as a method of preparing an emulsified preparation for intravenous injection.

[0002]

2. Description of the Related Art Fat emulsion
Is generally a lipid emulsion containing phospholipids and is a formulation developed for the purpose of supplementing calories in high calorie nutritional fluid therapy. The fat emulsion is basically soybean oil 10-
20% by weight, egg yolk or soybean lecithin (emulsifier) 1.
2-1.8 wt% and glycerin (tonicity agent) 2.5
It is an O / W type emulsion containing wt%. In addition to the basic formulation, fatty acids (emulsification aids), cholesterols (stabilizers), polymer substances, medicinal components, etc. may be added. The particle size of the emulsion is adjusted to 1.0 μm or less from the viewpoint of emulsion stability and prevention of intravascular thrombus.

Regarding the method for preparing the emulsified preparation as described above,
For example, JP-A-58-222014 and JP-A-60-1
No. 49524, Japanese Patent Laid-Open No. 2-101009, Japanese Patent Laid-Open No. 04
No. 69340, etc., all the fat-soluble components including the lecithin component and the water component (there is no isotonic component in some cases) are simultaneously mixed. Therefore, a part of lecithin does not collect at the interface, and an aggregate of lecithin alone is formed and dispersed, which does not play a role of emulsifying the fat-soluble component and the water component. Since a part of the added lecithin does not function as an emulsifier, it is impossible to obtain a product having a certain quality even as a formulation.

For example, lecithin, which is used as a raw material for emulsion for intravenous injection, is a solid in the form of powder, nougat, block or the like, which has a lamellar structure when directly suspended in water. Even if lecithin is present in oil, if it is dispersed in a crystalline state, a part of it will come into direct contact with water due to strong emulsification, and will have a lamellar structure. It is extremely difficult to transfer lecithin having a lamellar structure into oil again.
Since these lecithins are not effectively used for emulsification,
In order to maintain the emulsion stability, it is necessary to increase the amount of lecithin added. At the same time, the lamellar structure is more likely to be aggregated in blood than the emulsion, which leads to an increase in particle size and the occurrence of precipitation. Further, it may be possible to affect the pharmacological activity itself of the preparation.

Japanese Patent Publication No. 54-31485 discloses curry
A method for producing an emulsifying oil and fat to be used for producing roux, somen noodles, Chinese noodles, etc. or for improving the oil and fat content of drinking milk is described. In the case of adding lecithin to oil and fat to produce a homogeneous emulsifying oil and fat, it is an essential requirement to add 1% to 20% of ethanol to lecithin. However, ethanol addition is not a mandatory requirement for the amount added to oil. Looking at Examples and the like, it is about 0.05% to 6% with respect to the fat-soluble component. There is no mention of uses such as an intravenous emulsion.

Japanese Unexamined Patent Publication No. 4-338334 describes an invention relating to a prostaglandin E1 lipo preparation. As another production method, prostaglandin E1 is dissolved in an anhydrous organic solvent (preferably anhydrous ethanol etc.). It is described that 2 mg
Prostaglandin E1 in 200 μl absolute ethanol
And is mixed with 40 g of sesame oil in the Japanese Pharmacopoeia. However, the purpose of dissolving lecithin in ethanol in the present invention is to dissolve the lecithin in oils and fats relatively quickly even if the lecithin is heated, so that it is quickly dissolved in oils and fats. The purpose of use is different. The ethanol need not be anhydrous in the present invention. In the method described in the above publication, if the amount of ethanol used is large, the same effect as that of the present invention may be obtained as a result. However, as can be seen from the description such as "insert after emulsification", there is no treatment that considers the emulsified state of lecithin, and we recognize that it is a means to achieve this effect. I can't say.

[0007]

SUMMARY OF THE INVENTION The present invention aims to prepare a lecithin-containing fat emulsion which is a product of uniform quality.

[0008]

Means for Solving the Problems The present inventor has diligently studied the above-mentioned problems, and by utilizing lecithin effectively for emulsification, highly stable homogeneity like that of an intravenous emulsified preparation is required. It was found that in the product, the state of lecithin becomes uniform, and a product of uniform quality with no difference between lots can be prepared, and the present invention has been completed based on this finding.

The present invention is characterized in that, in a method for preparing a fat emulsion using lecithin as an emulsifier, lecithin and alcohol are added to and mixed with a fat and oil and a fat-soluble component, and then the mixture is mixed and emulsified with an aqueous component. This is a method for preparing a lipid emulsion.

The present invention provides that all of lecithin is effectively used to uniformly emulsify fats and oils in the preparation of lecithin-containing fat emulsion. For that purpose, the fats and oils and the fat-soluble components are made uniform in advance. To prevent lecithin from crystallizing during emulsification and separating into water, alcohol is added to fats and oils and fat-soluble components, and then the mixture is mixed and emulsified with water components. By adding alcohol in advance, it is possible to suppress the generation of the lamellar structure of lecithin. As a result, a stable emulsion can be obtained.

Further, by adding alcohol, stable emulsification in the normal temperature range becomes possible. Because the emulsification temperature using lecithin usually varies depending on the type of fats and oils used, the type and amount of fat-soluble components (fatty acids, fatty acid esters, sterols) added or originally contained, and water content, but it is generally 50 Relatively high above ℃. The emulsification at high temperature may lead to thermal decomposition and thermal deterioration of the components, but the addition of alcohol enables stable emulsification at room temperature. Usually, solid lecithin requires heating, a dispersing device and the like in order to dissolve it in a fat-soluble component, but when alcohol coexists, it becomes very easy to dissolve it in oil.

In the present invention, fats and oils are high-purity refined fats and oils and may be of any kind as long as they can be used in an intravenous emulsified preparation. For example, refined olive oil and refined soybean oil are insoluble by purification such as steam purification. Compound is 0.5% or less, preferably 0.1% or less.

In the present invention, lecithin is purified lecithin such as egg yolk lecithin and soybean lecithin, and can be prepared by a conventional fractionation method using an organic solvent. That is, for example, crude egg yolk phospholipid is dissolved in cold n-hexane-acetone, acetone is gradually added under stirring, insoluble matter is collected by filtration, and this operation is repeated once more, and then the solvent is distilled off. By doing so, purified lecithin can be obtained. This is mainly phosphatidylcholine,
It consists of phosphatidylethanolamine, and also contains phosphatidylinositol, phosphatidylserine, sphingomyelin and the like as other phospholipids. Further, the lecithin obtained here can be further fractionated by the difference in solubility in ethanol, or a specific component, mainly phosphatidylcholine, which is concentrated or isolated by column chromatography can be used.

Fat emulsion means 5 to 50% by weight of oil and fat, 1 of oil and fat.
Lecithin 1 to 50 parts, preferably 5 to 3 relative to 00 parts
It consists mainly of 0 parts and a suitable amount of water. Although the content of lecithin in the fat emulsion can be appropriately increased or decreased depending on the form and use of the emulsion, it is generally contained in the emulsion in an extremely small amount, for example, 0.5 to 50 mg / ml.

In the present invention, the alcohol added to prevent lecithin from crystallizing is ethanol,
Examples include methanol, isopropanol, and glycols. Preferably, the alcohol is ethanol or hydrous ethanol. Alcohol can be added to fats and oils as a solution of lecithin. When alcohol is added as a solution of lecithin to fats and oils, it is generally about the same amount as lecithin or more and about 10% or less with respect to the entire fat-soluble component. This is because if it exceeds 10%, the effect of emulsification inhibition by ethanol often occurs. From the viewpoint of the whole emulsion, it can be seen that even about 1% of oils and fats have a sufficient effect, and when it exceeds 5%, the effect of emulsification inhibition begins to appear. Depending on the composition of oil and fat, even a small amount may show a sufficient effect. In the case of an intravenous emulsion, if ethanol is used as alcohol, it is easily biodegraded and has no adverse effect on the human body. Even if such an amount of ethanol remains, the preparation and stability of the preparation may be good, but it is not bad.

In the method for producing a fat emulsion of the present invention, a predetermined amount of soybean oil, lecithin, fat-soluble components (fatty acid, fatty acid ester, sterols) and the like are mixed with alcohol to prepare a solution at room temperature, and then a required amount is added thereto. After adding water, a homogenizer suitable for fine emulsification (for example, pressure injection type homogenizer, ultrasonic homogenizer, etc.) is used after rough emulsification with an ordinary homogenizer (eg, TK homomixer, high speed stirring type such as Polytron). A homogenization treatment is carried out to obtain an oil-in-water emulsion. Depending on the production convenience, additives such as a stabilizer and an isotonic agent may be added after the formation of the fat emulsion.

Several emulsifying machines have long been known for the preparation of emulsions, but they have different atomizing abilities. Since the fat emulsion is a formulation which is directly administered intravenously, it is prepared as an emulsion having an average particle size of oil droplets of 0.2 to 0.3 μm in consideration of the size of blood vessels. Therefore, a high pressure homogenizer is essential for preparing a fat emulsion. Further, in order to maximize the performance of this high-pressure homogenizer, it is effective to perform atomization of about several μm as a pretreatment.
The particles are extremely fine and the average particle size is 1.0μ.
It is below, and the storage stability is very good.

The fatty acid having 6 to 22 carbon atoms as an emulsification aid can be used as long as it can be added to a pharmaceutical product. This fatty acid may be linear or branched, but linear stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, myristic acid or the like is preferably used. These salts include physiologically acceptable salts,
For example, an alkali metal salt (sodium salt, potassium salt, etc.) can be used. Cholesterol or phosphatidic acid as a stabilizer can be used as long as it can be used as a medicine.

The following are preferable as albumin, vinyl polymer and nonionic surfactant used as the polymer substance for the emulsion stabilizer. Human-derived albumin is used because of its antigenicity. Examples of the vinyl polymer include polyvinyl pyrrolidone. As the nonionic surfactant, polyalkylene glycol (for example, average molecular weight of 1000 to 10) is used.
000, preferably 4000-6000 polyethylene glycol), a polyoxyalkylene copolymer (for example, an average molecular weight of 1000-20,000, preferably 60).
00-10,000 polyoxyethylene-polyoxypropylene copolymer), hydrogenated castor oil polyoxyalkylene derivative (for example, hydrogenated castor oil polyoxyethylene- (40) -ether, the same- (20) -ether, the same-
(100) -ether and the like, castor oil polyoxyalkylene derivative (for example, castor oil polyoxyethylene- (20) -ether, same- (40) -ether, same-).
(100) -ether and the like can be used.

Examples of the drug include prostaglandin analogs such as prostaglandin E1, highly unsaturated fatty acid cascade hormones such as leukotriene, fat-soluble hormones such as steroid hormones such as gestagen, and adriamycin. Lipophilic anti-cancer agents, non-steroidal lipophilic analgesics such as ibuprofen, other lipophilic components and their derivatives that have a pharmacological effect, and lipid-insoluble derivatives of non-lipophilic drugs The drug which expresses is mentioned. Emulsions of these agents can be prepared by previously dissolving them in oils and fats, emulsifiers and other fat-soluble components, and then mixing and emulsifying with a water component.

[0021]

The details of the present invention will be described with reference to Examples. The present invention is not limited to these examples. In the following examples, the average particle size was measured by Zetasizer 3 (manufactured by Malvern, UK).

Example 1 100 g of refined olive oil (manufactured by Showa Sangyo Co., Ltd.) was mixed with 12 g of egg yolk lecithin (manufactured by Kewpie Co., Ltd.) and 10 ml of ethanol (manufactured absolute ethanol) at 20 ° C., and the mixture was adjusted to 20 ° C. Add glycerin isotonic solution to 1000
ml, and after roughly emulsifying with a stirring type homomixer, a total pressure of 600 using a high pressure emulsifying device (Mantongaulin type)
An emulsion was obtained by making 10 passes at kg / cm ² . The average particle size of this fat emulsion was 205 nm in distilled water,
Ultracentrifuged solids at 10,000 G were less than 1% of total solids. The rate of increase in particle size in serum after 1 day at 37 ° C. was 2%.

Example 2 Egg yolk phosphatidylcholine (Kewpie Co., Ltd. yolk lecithin) was used as a starting material in 100 g of purified soybean oil (Showa Sangyo Co., Ltd.) to isolate phosphatidylcholine by high performance liquid chromatography. 18 g) was dissolved in 10 ml of ethanol (95 vol.% Aqueous solution), 2.4 g of oleic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and 10 mg of adriamycin were mixed, and then ethanol was distilled off with a rotary evaporator. It took 2 hours to distill off ethanol.
It was 5 minutes. Glycerin isotonic solution heated to 50 ° C was added to this to make 1000 ml, and while maintaining at 50 ° C thereafter,
After roughly emulsifying with a stirring homomixer, a total pressure of 550 kg / c using a high pressure emulsifying device (Manton Gaulin type)
An emulsion was obtained by making 10 passes at m ² . The average particle size of this fat emulsion was 189 nm in distilled water, and the ultracentrifugation solid content at 100,000 G was 1% or less based on the total solid content. The rate of increase in particle size in serum after 1 day at 37 ° C. was 4%.

Comparative Example 1 100 g of refined olive oil (manufactured by Showa Sangyo Co., Ltd.) was mixed with 12 g of egg yolk lecithin (Kewpie Co., Ltd.) at 60 ° C. and then cooled to 20 ° C. Glycerin isotonic solution adjusted to 20 ° C. was added to make 1000 ml, and the mixture was roughly emulsified with a stirring homomixer and then subjected to 10 passes at a total pressure of 600 kg / cm ² using a high-pressure emulsifying device (Manton Gaulin type) to obtain an emulsion. Obtained. The average particle size of this fat emulsion is 21 in distilled water.
2 nm and ultracentrifuged precipitate solids at 100,000 G was 3.4% of total solids. The particle size increase rate in serum after 1 day at 37 ° C. was 20%.

Comparative Example 2 18 g of egg yolk phosphatidylcholine (one obtained by isolating phosphatidylcholine from high-performance liquid chromatography of egg yolk lecithin manufactured by Kewpie Co., Ltd.) in 100 g of refined soybean oil (Showa Sangyo Co., Ltd.). And 7 g of oleic acid 2.4 g
After uniformly mixing at 0 ° C., cooling to 30 ° C. and then adding glycerin isotonic solution heated to 30 ° C. to make 1000 ml, and roughly emulsifying with a stirring homomixer, then using a high pressure emulsifying device (Manton Gaulin type) 1 at a total pressure of 550 kg / cm ² .
The emulsion was obtained by passing 0 times. The average particle size of this fat emulsion was 217 nm in distilled water, and the ultracentrifugal precipitated solid content at 100,000 G was 3.3% of the total solid content. 37 ° C in serum
The particle size increase rate after 1 day was 30%.

Comparative Example 3 18 g of egg yolk phosphatidylcholine (one obtained by isolating phosphatidylcholine from yolk lecithin manufactured by Kewpie Co., Ltd. by high speed chromatography) in 100 g of refined soybean oil (Showa Sangyo Co., Ltd.) and Oleic acid (Wako Pure Chemical Industries, Ltd.)
2.4 g) was stirred and mixed, and the same temperature was applied by a rotary evaporator for the same time as in Example 3. Add glycerin isotonic solution heated to 50 ℃ to this and add 1000 ml.
And after roughly emulsifying with a stirring homomixer at 50 ° C.,
Total pressure 55 using high pressure emulsifier (Manton Gaulin type)
An emulsion was obtained by making 10 passes at 0 kg / cm ² . The average particle size of this fat emulsion was 255 nm in distilled water.
The ultracentrifuged solids at 0,000 G was 2.1% of total solids. The increase in particle size in serum after 1 day at 37 ° C. was 110%.

[0027]

In the preparation of the lecithin-containing fat emulsion,
Generation of a lamellar structure of the raw material lecithin can be suppressed and a stable emulsion can be prepared. It is possible to prepare a lecithin-containing fat emulsion, which is a product of uniform quality that is not affected by the state of existence of the raw material lecithin (liquid crystal, solid, etc.) and is not different between lots.

Claims (7)

[Claims] 1. A method for preparing a fat emulsion using lecithin as an emulsifier, which comprises adding and mixing lecithin and alcohol to fats and oils and a fat-soluble component, and then mixing and emulsifying the mixture with an aqueous component. Law. 2. The method for preparing a fat emulsion according to claim 1, wherein the lecithin and alcohol are an alcohol solution of lecithin. 3. The method for preparing a fat emulsion according to claim 1, wherein the alcohol is ethanol or hydrous ethanol. 4. The method according to claim 1, wherein the amount of ethanol is 0.1 to 10% by weight based on the fat and oil and the fat-soluble component.
Alternatively, the method for preparing a fat emulsion according to claim 3. 5. The amount of ethanol is 0.
The method for preparing a fat emulsion according to claim 1, claim 2, claim 3 or claim 4, wherein the content is 5% by weight or less. 6. The method for preparing a fat emulsion according to claim 1, claim 2, claim 3, claim 4 or claim 5, wherein the fat emulsion is an intravenous preparation. 7. The method for preparing a fat emulsion according to claim 1, claim 2, claim 3, claim 4 or claim 5, wherein the fat emulsion is a drug carrier.